Cooperative interaction of Nkx2.5 and Mef2c transcription factors during heart development

Joshua W. Vincentz, Ralston M. Barnes, Beth A. Firulli, Simon J. Conway, Anthony B. Firulli

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

The interactions of diverse transcription factors mediate the molecular programs that regulate mammalian heart development. Among these, Nkx2.5 and the Mef2c regulate common downstream targets and exhibit striking phenotypic similarities when disrupted, suggesting a potential interaction during heart development. Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c. Assessment of mRNA expression verified spatiotemporal cardiac coexpression. Finally, genetic interaction studies employing histological and molecular analyses showed that, although Nkx2.5-/- and Mef2c-/- individual mutants both have identifiable ventricles, Nkx2.5-/-;Mef2c-/- double mutants do not, and that mutant cardiomyocytes express only atrial and second heart field markers. Molecular marker and cell death and proliferation analyses provide evidence that ventricular hypoplasia is the result of defective ventricular cell differentiation. Collectively, these data support a hypothesis where physical, functional, and genetic interactions between Nkx2.5 and Mef2c are necessary for ventricle formation.

Original languageEnglish (US)
Pages (from-to)3809-3819
Number of pages11
JournalDevelopmental Dynamics
Volume237
Issue number12
DOIs
StatePublished - Dec 1 2008

Keywords

  • Heart development
  • Mef2c
  • Mouse
  • Nkx2.5
  • Ventricle

ASJC Scopus subject areas

  • Developmental Biology

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